title: Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid.
abstract: Although death receptors and chemotherapeutic drugs activate distinct apoptosis signaling cascades, crosstalk between the extrinsic and intrinsic apoptosis pathway has been recognized as an important amplification mechanism. Best known in this regard is the amplification of the Fas (CD95) signal in hepatocytes via caspase 8-mediated cleavage of Bid and activation of the mitochondrial apoptosis pathway. Recent evidence, however, indicates that activation of other BH3-only proteins may also be critical for the crosstalk between death receptors and mitochondrial triggers. In this study, we show that TNF-related apoptosis-inducing ligand (TRAIL) and chemotherapeutic drugs synergistically induce apoptosis in various transformed and untransformed liver-derived cell lines, as well as in primary human hepatocytes. Both, preincubation with TRAIL as well as chemotherapeutic drugs could sensitize cells for apoptosis induction by the other respective trigger. TRAIL induced a strong and long lasting activation of Jun kinase, and activation of the BH3-only protein Bim. Consequently, synergistic induction of apoptosis by TRAIL and chemotherapeutic drugs was dependent on Jun kinase activity, and expression of Bim and Bid. These findings confirm a previously defined role of TRAIL and Bim in the regulation of hepatocyte apoptosis, and demonstrate that the TRAIL-Jun kinase-Bim axis is a major and important apoptosis amplification pathway in primary hepatocytes and liver tumor cells.
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Schneider-Jakob
authors.forename: N
authors.initials: N
authors.lastname: Corazza
authors.forename: A
authors.initials: A
authors.lastname: Badmann
authors.forename: D
authors.initials: D
authors.lastname: Sidler
authors.forename: R
authors.initials: R
authors.lastname: Stuber-Roos
authors.forename: A
authors.initials: A
authors.lastname: Keogh
authors.forename: S
authors.initials: S
authors.lastname: Frese
authors.forename: M
authors.initials: M
authors.lastname: Tschan
authors.forename: T
authors.initials: T
authors.lastname: Brunner
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D004317:Doxorubicin / Q000627:therapeutic use*; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy*; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases